Tumor is one of the malignant diseases that threaten human health. Every year, more than 5,000,000 peoples die for tumors throughout the world. In China, more than 1,600,000 peoples are newly found to be sufferring from tumors and the peoples died for them have exceeded 1,300,000 each year. Hence, it has been a worldwide focus to develop anti-cancer medicaments.
Vinca alkaloids anti-tumor agents are a type of bisindole alkaloids having anti-cancer activities. They are isolated from Catharanthus roseus (L.) G. Don and Catharanthus roseus (L.) G. Don cv. Flavus which are perivinkle plants of Apocynaceae family. Natural Vinca alkaloids can be biosynthesized through coupling catharanthine and vindoline, which are mono-indole alkaloids rich in the plants.
Currently, there are four Vinca alkaloids or derivatives thereof in clinical use, i.e., vinblastine (VLB), vincristine (VCR), vindesine (VDS) and vinorelbine (NVB).
Vinca alkaloids anti-tumor agents are cell cycle specific agents that mainly function in the G2 phase (post-synthetic phase of DNA) of tumor cells. It is reported that the mechanism of action of Vinca alkaloids anti-tumor agents are that they bind with tubulin inhibiting the formation of microtubules from the polymerization of tublin dimers, and also induce the disruption of the cytoskeleton blocking the formation of mitotic spindles and arresting the tumor cell divison and proliferation at mitotic metaphase, and thus exhibit the antineoplastic activity (R. J. Owellen and C. A. Hartke, Cancer Res., 1976, 36, 1499-1504; R. N. Kersey, Cancer Res., 1976, 36, 3798-3806; R. S. Camplrjohn, Cell Tissue Kinet., 1980, 13, 327-332). The tubulin binding affinity of Vinca alkaloids anti-tumor agents has a poorly linear correlation with their inhibiting activities against cell growth. It is generally considered that the differences of the activities and side effects among Vinca alkaloids anti-tumor agents are mainly resulted from the differences of their uptake and retention in tumor tissues.
A small change in the structure of a vinblastine analog may cause great variation in its anti-tumor spectra and toxicity and side effect spectra. For example, the only difference between vinblastine and vincristine is that a N-methyl group is substituted by a N-aldehyde group. However, vincristine exhits good inhibiting activity against Rhabdoid Tumors in vivo, and vinblastine shows no efficacy. In addition, they are completely different in their toxicity spectra. The major toxiticies are peripheral neurotoxicity for vincristine and anaemia and reduction of leucocyte for vinblastine (N. Bruchovsky et al., Cancer Res. 1965, 25, 1232-1238). Vinorelbine has a poorer inhibiting activity on P388 and L1210 cell lines than vinblastine and vincristine, but a better inhibiting activity on lung cancer than other vinblastine analogs. Therefore, it has been a first-line agent for treating clinically nonsmall-cell lung cancers (S. Cros, et al., Seminars in Oncology, 1989, 16, 15-20).
Therefore, there is a need to develop novel vinblastine derivatives with better anti-tumor activities and reduced toxicity and side effects through designing and sysnthesizing a series of new derivatives based on the research results on the structure-activity relationship, followed by extensive biologic assay in vitro and in vivo, since the anti-tumor activities of vinblastine analogs in vivo lack direct relation with that in vitro, and a small change in the structures of vinblastine analogs may result in great difference in their anti-tumor sprectra and toxicity sprectra. The present inventors have found novel vinblastine derivatives with strong anti-tumor activity through synthesizing a series of vinblastine analogs by coupling a modified vindoline with a catharanthine, followed by evalutated in vivo and in vitro.